Oxidative stress signaling and regulated cell death in Parkinson's disease

Vélez-Pardo, Carlos; Jiménez-Del-Río, Marlene

doi:10.1016/b978-0-12-815950-7.00010-2

Cited by 4 publications

(2 citation statements)

References 60 publications

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“…Previous studies have shown that ROT-induced apoptosis in neuron-like cells and non-neuronal cells (e.g., HEK-293 cells) occurs through OS mechanisms involving the loss of ∆Ψ m , generation of H 2 O 2 , oxidation of DJ-1 into DJ-1Cys 106 -SO 3 , increased expression of PRKN, phosphorylated LRRK2 at residue Ser 935 , phosphorylated α-Syn at residue Ser 129 , mitochondrial colocalization of DRP1 and TOMM20, and appearance of cleaved caspase 3 (CC3) as a sign of the activation of CASP3 and apoptosis [40,70,71]. Here, we confirm that ROT induced a dose (10 and 50 µM)and time (6 and 24 h)-dependent OS mechanism in DALNs involving positive detection of all OS and apoptotic markers such as ∆Ψ m , DJ-1Cys 106 -SO 3 /(H 2 O 2 ), DRP1/TOMM20 and PRKN, p-Ser 935 -LRRK2, p-Ser 129 -α-Syn and CC3 (Table 1).…”

Section: Discussionmentioning

confidence: 99%

High Yield of Functional Dopamine-like Neurons Obtained in NeuroForsk 2.0 Medium to Study Acute and Chronic Rotenone Effects on Oxidative Stress, Autophagy, and Apoptosis

Quintero-Espinosa,

Velez-Pardo,

Jimenez-Del-Rio

2023

IJMS

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Several efforts to develop new protocols to differentiate in in vitro human mesenchymal stromal cells (hMSCs) into dopamine (DA) neurons have been reported. We have formulated NeuroForsk 2.0 medium containing fibroblast growth factor type beta (FGFb), brain-derived neurotrophic factor (BDNF), melatonin, purmorphamine, and forskolin. We report for the first time that menstrual stromal cells (MenSCs) cultured in NeuroForsk 2.0 medium for 7 days transdifferentiated into DA-like neurons (DALNs) expressing specific DA lineage markers tyrosine hydroxylase-positive cells (TH+) and DA transporter-positive (DAT+) cells and were responsive to DA-induced transient Ca2+ influx. To test the usefulness of this medium, DALNs were exposed to rotenone (ROT), a naturally occurring organic neurotoxin used extensively to chemically induce an in vitro model of Parkinson’s disease (PD), which is a movement disorder characterized by the specific loss of DA neurons. We wanted to determine whether ROT induces apoptotic cell death and autophagy pathway under acute or chronic conditions in DALNs. Here, we report that acute ROT exposure induced several molecular changes in DALNS. ROT induced a loss of mitochondrial membrane potential (ΔΨm), high expression of parkin (PRKN), and high colocalization of dynamin-related protein 1 (DRP1) with the mitochondrial translocase of the outer membrane of mitochondria 20 (TOMM20) protein. Acute ROT also induced the appearance of DJ-1Cys106-SO3, as evidenced by the generation of H2O2 and oxidative stress (OS) damage. Remarkably, ROT triggered the phosphorylation of leucine-rich repeat kinase 2 (LRRK2) at residue Ser935 and phosphorylation of α-Syn at residue Ser129, a pathological indicator. ROT induced the accumulation of lipidated microtubule-associated protein 1B-light chain 3 (LC3B), a highly specific marker of autophagosomes. Finally, ROT induced cleaved caspase 3 (CC3), a marker of activated caspase 3 (CASP3) in apoptotic DALNs compared to untreated DANLs. However, the chronic condition was better at inducing the accumulation of lysosomes than the acute condition. Importantly, the inhibitor of the LRRK2 kinase PF-06447475 (PF-475) almost completely blunted ROT-induced apoptosis and reduced ROT-induced accumulation of lysosomes in both acute and chronic conditions in DALNs. Our data suggest that LRRK2 kinase regulated both apoptotic cell death and autophagy in DALNs under OS. Given that defects in mitochondrial complex I activity are commonly observed in PD, ROT works well as a chemical model of PD in both acute and chronic conditions. Therefore, prevention and treatment therapy should be guided to relieve DALNs from mitochondrial damage and OS, two of the most important triggers in the apoptotic cell death of DALNs.

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Section: Discussionmentioning

confidence: 99%

High Yield of Functional Dopamine-like Neurons Obtained in NeuroForsk 2.0 Medium to Study Acute and Chronic Rotenone Effects on Oxidative Stress, Autophagy, and Apoptosis

Quintero-Espinosa,

Velez-Pardo,

Jimenez-Del-Rio

2023

IJMS

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“…Moreover, it has been shown that reduced expression of Lrrk by knocking down (KD) the Lrrk gene in DAergic neurons of Drosophila melanogaster conferred resistance to PQ intoxication, thereby increasing locomotor activity, extending lifespan, and reducing OS 32 . Therefore, LRRK2 is a relevant kinase associated with OS signaling, neurodegeneration, and apoptosis in PD 33 . However, no data are available to establish whether PQ + MB affects the survival of NLCs.…”

Section: Introductionmentioning

confidence: 99%

Phenolic‐rich extract of avocado Persea americana (var. Colinred) peel blunts paraquat/maneb‐induced apoptosis through blocking phosphorylation of LRRK2 kinase in human nerve‐like cells

Quintero-Espinosa

Ortega-Arellano

Vélez-Pardo

et al. 2021

Environmental Toxicology

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It is increasingly evident that LRRK2 kinase activity is involved in oxidative stress (OS)‐induced apoptosis—a type of regulated cell death and neurodegeneration, suggesting LRRK2 inhibition as a potential therapeutic target. We report that a phenolic‐rich extract of avocado Persea americana var. Colinred peel (CRE, 0.01 mg/ml) restricts environmental neurotoxins paraquat (1 mM)/maneb (0.05 mM)‐induced apoptosis process through blocking reactive oxygen species (ROS) signaling and concomitant inhibition of phosphorylation of LRRK2 in nerve‐like cells (NLCs). Indeed, PQ + MB at 6 h exposure significantly increased ROS (57 ± 5%), oxidation of protein DJ‐1cys106SOH into DJ‐1Cys106SO3 ([~3.7 f(old)‐(i)ncrease]), augmented p‐(S935)‐LRRK2 kinase (~20‐f(old) (i)ncrease), induced nuclei condensation/fragmentation (28 ± 6%), increased the expression of PUMA (~6.2‐fi), and activated CASPASE‐3 (CASP‐3, ~4‐fi) proteins; but significantly decreased mitochondrial membrane potential (ΔΨm, ~48 ± 4%), all markers indicative of apoptosis compared to untreated cells. Remarkably, CRE significantly diminished both OS‐signals (i.e., DCF+ cells, DJ‐1Cys106SO3) as well as apoptosis markers (e.g., PUMA, CASP‐3, loss of ΔΨm, p‐LRRK2 kinase) in NLCs exposed to PQ + MB. Furthermore, CRE dramatically reestablishes the transient intracellular Ca2+ flow (~300%) triggered by dopamine (DA) in neuronal cells exposed to PQ + MB. We conclude that PQ + MB‐induced apoptosis in NLCs through OS‐mechanism, involving DJ‐1, PUMA, CASP‐3, LRRK2 kinase, mitochondria damage, DNA fragmentation, and alteration of DA‐receptors. Our findings imply that CRE protects NLCs directly via antioxidant mechanism and indirectly by blocking LRRK2 kinase against PQ + MB stress stimuli. These data suggest that CRE might be a potential natural antioxidant.

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Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson’s Disease Dementia (PDD)

Giraldo-Berrio,

Mendivil-Perez,

Velez-Pardo

et al. 2024

Neurotox Res

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Parkinson’s disease with dementia (PDD) is a neurological disorder that clinically and neuropathologically overlaps with Parkinson’s disease (PD) and Alzheimer’s disease (AD). Although it is assumed that alpha-synuclein ($$\mathrm{\alpha }$$ α -Syn), amyloid beta (A$$\upbeta$$ β ), and the protein Tau might synergistically induce cholinergic neuronal degeneration, presently the pathological mechanism of PDD remains unclear. Therefore, it is essential to delve into the cellular and molecular aspects of this neurological entity to identify potential targets for prevention and treatment strategies. Cholinergic-like neurons (ChLNs) were exposed to rotenone (ROT, 10$$\upmu$$ μ M) for 24 h. ROT provokes loss of $$\Delta \mathrm{\Psi m}$$ Δ Ψ m , generation of reactive oxygen species (ROS), phosphorylation of leucine-rich repeated kinase 2 (LRRK2 at Ser935) concomitantly with phosphorylation of $$\mathrm{\alpha }$$ α -synuclein ($$\mathrm{\alpha }$$ α -Syn, Ser129), induces accumulation of intracellular A$$\upbeta$$ β (iA$$\upbeta$$ β ), oxidized DJ-1 (Cys106), as well as phosphorylation of TAU (Ser202/Thr205), increases the phosphorylation of c-JUN (Ser63/Ser73), and increases expression of proapoptotic proteins TP53, PUMA, and cleaved caspase 3 (CC3) in ChLNs. These neuropathological features resemble those reproduced in presenilin 1 (PSEN1) E280A ChLNs. Interestingly, anti-oxidant and anti-amyloid cannabidiol (CBD), JNK inhibitor SP600125 (SP), TP53 inhibitor pifithrin-$$\mathrm{ \alpha }$$ α (PFT), and LRRK2 kinase inhibitor PF-06447475 (PF475) significantly diminish ROT-induced oxidative stress (OS), proteinaceous, and cell death markers in ChLNs compared to naïve ChLNs. In conclusion, ROT induces p-$$\mathrm{ \alpha }$$ α -Syn, iA$$\upbeta$$ β , p-Tau, and cell death in ChLNs, recapitulating the neuropathology findings in PDD. Our report provides an excellent in vitro model to test for potential therapeutic strategies against PDD. Our data suggest that ROT induces a neuropathologic phenotype in ChLNs similar to that caused by the mutation PSEN1 E280A.

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Oxidative stress signaling and regulated cell death in Parkinson's disease

Cited by 4 publications

References 60 publications

High Yield of Functional Dopamine-like Neurons Obtained in NeuroForsk 2.0 Medium to Study Acute and Chronic Rotenone Effects on Oxidative Stress, Autophagy, and Apoptosis

High Yield of Functional Dopamine-like Neurons Obtained in NeuroForsk 2.0 Medium to Study Acute and Chronic Rotenone Effects on Oxidative Stress, Autophagy, and Apoptosis

Phenolic‐rich extract of avocado Persea americana (var. Colinred) peel blunts paraquat/maneb‐induced apoptosis through blocking phosphorylation of LRRK2 kinase in human nerve‐like cells

Rotenone Induces a Neuropathological Phenotype in Cholinergic-like Neurons Resembling Parkinson’s Disease Dementia (PDD)

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